A cutaneous scar is the outcome of the repair processes that restore the continuity of damaged skin. Normally, this repair process leads to the formation of new tissue with a visibly different appearance from the surrounding skin. In particular, scar tissue may lack pigmentation, or have too much, or be depressed, shiny, rough, normotrophic, retracted or lacking in elasticity. At a microscopic level, scar tissue is characterized by an abundant and disorganized deposit of collagen arranged in thick, dense, twisted bundles. The scarring process is very lengthy, as the reshaping phase remains active for years. In some cases, during the initial reshaping phase, the scarring process may become pathological, giving rise to hypertrophic scars or keloids. Hypertrophic scars are characterized by excessive thickening, but without any spreading beyond the wound area. Conversely, in the case of keloids, besides the thickening of the newly formed tissue, there is colonization of the surrounding area too. The formation of both hypertrophic scars and keloids seems to involve an imbalance of immune system. From a histological point of view, they are both characterized by a moderate amount of cell infiltration and by an excessive and disorganized deposit of thick bundles of collagen. Scars may cause functional difficulties and are unsightly. The chief functional difficulties occur when the scar forms on critical areas of skin such as at the joints. In this case, the poor elasticity of scar tissue may lead to incorrect functioning of the joint itself.
Normal wound healing in response to tissue injury involves several integrated processes: inflammation, production of granulation tissue, formation of the extracellular matrix, wound contraction, and, finally, scar formation. In the final phases of wound healing, fibroblasts degrade and produce bundles of collagen fibers. These bundles become thicker and are aligned along the lines of tension to which the tissues are exposed. As a result of these changes, wound tensile strength gradually increases. The resulting scar is relatively acellular and has fewer macrophages, blood vessels, and fibroblasts than the unwounded tissue.
Scars may be normotrophic, atrophic, hypertrophic, or keloidal. Both hypertrophic and keloidal scars are abnormal responses to tissue injury. Hypertrophic scars mature and flatten over time, usually after 6 months. The keloid appears as a shiny, smooth, raised proliferation of scar tissue with typical crablike extensions beyond the site of the original injury Keloids differ from hypertrophic scars in that their development is delayed, sometimes occurring months after tissue injury. Keloids do not regress, and they frequently cause pain, itching, and burning. Keloids are more common in African Americans, Hispanics, and persons with a personal or family history of keloids.
In atrophic scars, there is thinning of the skin and loss of normal architecture. Striae distensae, a so-called stretch mark, is a common dermal atrophic scar that tends to appear during periods of rapid weight gain and in the presence of excess glucocorticoid, as well as late in gestation.
Treatment with intralesional steroids, 10 to 40 mg/ml once a month for up to 6 months, can effectively flatten keloid and hypertrophic scars. Cryotherapy (a 30-second application once a month for 3 months) has been found to be safe and effective. Topical silicone gel sheeting, which was first used for burn scars, has been used in the treatment of keloids and hypertrophic scars. There is no release of silicone into the skin, and there are no adverse side effects from this treatment. The mechanism of action is unknown. Potential side effects of intralesional corticosteroid treatment include atrophy, depigmentation, telangiectasia, and ulceration and dose-related systemic effects.
Keloids are proliferative dermal growths that develop after skin injury. Unlike hypertrophic scars, the scar tissue extends beyond the borders of the original wound. The first description of keloids was offered in the Smyth papyrus on surgical techniques in Egypt 1700 BC. Subsequently, Alibert in 1806 used the term “cheloide”, derived from the Greek “chele” or crab claw to describe the lateral growth of tissue into normal skin. In addition to the cosmetic disfigurement these scars represent to affected patients, they can be pruritic, tender and can be complicated by secondary infections.
Keloids occur most commonly between the ages of 10 and 30 years. Deeply pigmented people are more susceptible to proliferative scarring than those with fair skin. Keloid formation correlates with sites where melanocyte concentrations are greatest. In addition, pregnancy and puberty, times of increased physiologic pituitary activity, have been associated with increased keloid formation. Incidence has been reported at 4.5 and 16% in black and Hispanic populations respectively. Definitive incidence figures are not known for hypertrophic scars. Inheritance patterns of keloids are autosomal dominant and autosomal recessive and they have been genetically associated with HLA B14, B21, Bw16, Bw35, DR5, and DQw3.
Keloids differ from hypertrophic scars clinically and histologically. Clinically, keloids are a deep red or purple color with raised indurated tissue that extends beyond the original wound borders. Hypertrophic scars have a less impressive white or pink color, with firm tissue limited to original wound border. Histologically, keloids are composed of disorganized thick hyalinized collagen with a prominent mucoid matrix, whereas hypertrophic scars are characterized by fewer, more organized collagen fibers with a scanty mucoid matrix. The fibroblast concentration is more prominent in hypertrophic scars. Hypertrophic and keloidal scarring is more common in darkly pigmented races. There is increased proliferative scarring during increased hormonal stimulation. Keloids are characterized by more disorganized, thickened collagen fibers and a prominent mucoid matrix.
Moreover, the aesthetic problems due to scar formation must not be underestimated, as scarring often causes psychological disorders, especially when it affects the face.
The methods used to date to make scars less visible are of a surgical nature, such as the technique using expanded strips of skin. This technique involves the expansion of areas of skin by subcutaneous agents. Once a sufficient amount of skin has been obtained to cover the scarred area, the scar is surgically removed and the expanded skin is grafted into place.
To date, there have been no efficacious pharmacological therapies to cure normotrophic scarring, pathological scarring can be treated pharmacologically using cortisone derivatives and, in some cases, strong immunosuppressors such as cyclosporin. In order to improve the elasticity of the scar tissue and induce its reabsorption, softening compositions are used such as creams and adhesive silicon films for prolonged application. Besides said topical treatments, patients undergo therapies with instruments designed to massage the scarred area by aspiration, to re-establish its elasticity and softness. Said remedies, however, have various disadvantages such as the need to perform one or more operations on the patient and, in the case of pharmacological therapy, their limitation to the treatment of pathological scarring and their unproven efficacy. Lastly, the products for topical use and therapeutic practices give fairly good results with regard to functionality, but poor aesthetic results.
It is well known that daily administration of hyaluronic acid can lead to scar-free tissue repair in a foetal animal model and that this glycosaminoglycan plays an important role in skin reconstruction. Moreover, technical experience has taught us that long-term high quantities of hyaluronic acid create one of the fundamental conditions to obtain scar-free skin repair (West D. C. et al., J. Biochem. Cell Biol. 1997, 29, 201-210, Iocono J. A., J. Pediatric Surg. 1998, 33, 564-567).
Hyaluronic acid is a polysaccharide ether composed of alternating residues of D-glucuronic acid and N-acetyl-D-glycosamine. It is a straight-chain polymer with a molecular weight which may vary between 50,000 and 13,000,000 Da, according to the source from which it was obtained and the methods of preparation which were used. It is present in nature in the pericellular gels, in the fundamental substance of the connective tissue of vertebrae organisms of which it represents one of the main components, in the synovial fluid of joints, in the vitreous humor, in the tissues of human umbilical cord and in rooster combs.
In recent years, various types of hyaluronic derivatives have been synthesized to obtain compounds with pharmacological properties or which can be processed in various forms of biodegradable and biocompatible biomaterials for use in the various fields of medicine, surgery and tissue engineering.
For example, the total or partial esters of hyaluronic acid and the autocross-linked derivatives of hyaluronic acid are known, as is their use in the pharmaceutical, cosmetic field an in that of biodegradable materials (U.S. Pat. Nos. 4,851,521; 4,965,353; 5,676,964).
Moreover, hyaluronic acid derivatives have new properties which starting hyaluronic acid does not have, due to the insertion of specific molecules in their structure. For example, the sulphated derivatives of hyaluronic acid present anticoagulant properties and are resistant to hyaluronidase (WO 95/25751, WO 98/45335).
Lastly, the use of N-sulphated derivatives in the prevention of pathological scarring such as hypertrophic scarring and keloids is known. However, said derivatives have never been reported as being able to prevent the formation of normotrophic scarring.
It has now been found, surprisingly, that hyaluronic acid derivatives are efficacious in reducing the extent of normotrophic scarring and that said activity is greater than that of hyaluronic acid itself.